Diseases of metabolic dysregulation are major public health concerns in the developing world. Obesity is associated with multiple health problems and is being recognized as a growing epidemic, while incidence of Type II diabetes continues to rise. Many derangements in the gut-to-brain axis, or the response of central neural pathways to information from the digestive system, have been implicated in obesity and Type II diabetes. However, relatively little is known about the pathways by which information from the periphery reaches these central homeostatic sites. Several lines of evidence suggest that the afferent vagal nerve may play a key role in neural regulation of energy homeostasis. Uncovering these pathways may result in new targets for treatment of energy balance dysfunction. The studies proposed here seek to, using a combination of genetic and pharmacologic manipulations in mice which allow for specific ablation of vagal sensory neurons, determine whether vagal afferents are required for the maintenance of long-term body weight and glucose homeostasis under chow feeding and in diet-induced obesity, if vagal afferents are required for the anti-diabetic actions of thiazolidinediones, and if vagal afferents are necessary for the anti-diabetic action of the CB1R antagonist class of drugs. PUBLIC HEALTH RELEVANCE: Relevance Obesity and diabetes are now epidemic in the United States, and if left unchecked, the growing rate of these diseases will cause a tremendous increase in morbidity and mortality, as well as ensuing health care costs. However, few effective pharmacological therapies for obesity exist. By examining the role of vagal sensory neurons in maintenance of body weight and glucose homeostasis, the studies proposed here could result in a new target for treatment of diseases of metabolic dysregulation.